Abstract 126: Susceptibility To Social Stress Modulates Hematopoiesis And Impairs Atherosclerosis Resolution

Abstract

Background: Depressive disorders frequently involve prolonged stress and are associated with increased risk of cardiovascular disease (CVD). A major hurdle in gaining mechanistic insight is the paucity of animal models that accurately recapitulate the symptoms of depression disorders. The major question we investigated was whether psychological stress impairs the benefits of the common therapy used to reduce CV risk, namely, lipid lowering. Methods: We employed a standard protocol of repeated social defeat stress (RSDS) that elicits a depression-like phenotype in mice to test the effects on atherosclerosis resolution. LDLr-deficient mice were kept on an atherogenic diet for 24 wks. Then RSDS was applied for 10 days. Mice that developed a depressive-like phenotype, termed stress susceptible (SS), were identified with behavior testing. SS and control mice were then placed on cholesterol-reducing therapy. Results: SS mice vs. control mice had expansion of bone marrow (BM) myeloid progenitors (~80% increase for GMP cells; P<0.001) and more circulating monocytes (~2X; P <0.05), which exhibited higher recruitment (2.5X; P <0.001) to atherosclerotic plaques. This resulted in increased (~50%; P <0.05) plaque macrophage content after 3 wks of cholesterol lowering. To investigate whether the effects of RSDS on inflammation and atherosclerosis were mediated by re-programming of the BM progenitors of plaque macrophages, we performed BM transplantation from control or SS mice into LDLr-deficient mice. After the recovery period, the mice were fed an atherogenic diet for 24 wks. At that time, we found that compared to control BM recipients, SS BM recipients sustained the increase in myeloid progenitors (~16% increase, P<0.05 for GMP population) and circulating inflammatory monocytes (50% increase; P <0.001), as well as enhanced atherosclerotic plaque inflammation (23% more macrophage content; P<0.001). Conclusions: Social stress impairs atherosclerosis inflammation resolution after cholesterol lowering, apparently by re-programming BM precursors of plaque macrophages. By applying molecular methods to this model, we hope to further understand the mechanistic basis for the increase in CVD risk in stressed people despite risk reducing therapies.